Ocular pharmacokinetics of subconjunctivally administered cyclosporine in the rabbit.

The authors assessed the ocular toxicity and pharmacokinetics of subconjunctivally and intravenously administered cyclosporine in New Zealand white rabbits. Fifteen rabbits received a subconjunctival injection of 5 (five animals), 10 (five animals) or 25 (five animals) mg of cyclosporine in 0.1 mL (intravenous solution of Sandimmune [50 mg/mL]); 5 mg was found to be the maximum tolerable dose. This dose was given as a bolus to 36 other rabbits either subconjunctivally (18 animals) or intravenously (18 animals). In both groups the cyclosporine concentrations in the ocular compartments, blood and urine were measured by means of high-pressure liquid chromatography at 0.5, 1, 2, 4, 8 and 12 hours, three animals being assessed at each interval. Subconjunctival administration resulted in peak cyclosporine concentrations of 718 ng/mL in the aqueous humour and 1078 ng/mL in the vitreous humour, compared with no detectable levels in the aqueous humour and a peak concentration of 292 ng/mL in the vitreous following intravenous administration. The peak blood cyclosporine levels were 10 times lower after subconjunctival injection than after intravenous injection. The results indicate that subconjunctival administration is superior to intravenous administration in enhancing the ocular absorption of cyclosporine while minimizing systemic exposure in the rabbit.

Effect of subconjunctivally administered antineoplastics on experimentally induced intraocular malignant tumour.

Twice-weekly subconjunctival injections of 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), cytarabine (ARA-C) and methotrexate (12.5 mg, 20 mg, 75 mg and 12.5 mg per dose respectively) were used to treat Greene melanoma implanted in the anterior chamber of the eyes of three groups of New Zealand rabbits: group 1 (14 animals), the control group, received saline, group 2 (16 animals) received treatment beginning immediately after tumour implantation and group 3 (15 animals) received treatment starting 1 week after implantation. Both 5-FU and 6-MP were effective in delaying iris tumour growth, as judged by daily clinical examination, histopathological study and reduction in tumour weight compared with control eyes after 17 days (group 2: p less than 0.001, p less than 0.05; group 3: p less than 0.025, p less than 0.05). The delay was correlated with earlier onset of treatment (group 2 v. 3: 5-FU, p less than 0.025; 6-MP, p less than 0.05). ARA-C and methotrexate were ineffective at the dosages used. Our results suggest that subconjunctivally administered 5-FU and 6-MP significantly delay tumour growth in this experimental model of iris melanoma and that efficacy is correlated with earlier initiation of treatment.

Cyclic alternating chemotherapy for small cell carcinoma of the lung.

Eighty-two previously untreated patients with small cell cancer of the lung were treated with six cycles of two alternating drug regimens: a new combination of mitomycin, methotrexate, and etoposide; and cyclophosphamide, doxorubicin, and vincristine. No maintenance chemotherapy was used. Consolidative thoracic irradiation and prophylactic cranial irradiation were employed. The median survival time for 32 limited-disease patients was 59 weeks, and for 50 extensive-disease patients was 35 weeks. Four-year survival was 12% for limited-disease patients and 2% for extensive-disease patients. These results were not superior to conventional combination chemotherapy regimens.

Ocular absorption and toxicity of methotrexate in the dog.

The ocular absorption, elimination and toxicity of 12.5 mg of methotrexate in 0.5 cc administered subconjunctivally was studied in the dog. The purpose of this study was to establish ocular pharmacokinetics for treatment of intraocular tumours in dogs. Drug levels were measured in ocular compartments, and serum at 1,2,4,6,8 and 12 hours respectively. Tumoricidal concentrations of the drug were attained in the anterior chambers of the injected eyes up to and including six hours postinjection. Consistent signs of toxicity were anorexia, vomiting, weight loss and leukopenia. Local ocular toxicity following subconjunctival injection was minimal conjunctival hyperemia lasting up to 48 hours.

5-FU infusion in advanced colorectal cancer: a comparison of three dose schedules.

Ninety-four patients with advanced colorectal adenocarcinoma were treated by continuous iv 5-FU infusion on three different dose schedules. Thirty-three patients received a 72-hour infusion of 5-FU (30 mg/kg/24 hours) every 3 weeks (Group A); 31 received a 72-hour infusion of 5-FU (30 mg/kg/24 hours) every 2 weeks (Group B); and 30 received a 48-hour infusion of 5-FU (30 mg/kg/24 hours) every week (Group C). Although this was a sequential nonrandomized study of the dose schedules, the groups were comparable with respect to various prognostic factors. Response rates were as follows: Group A--three patients had minor response (9%) and 30 had no response (91%); Group B--five patients achieved partial response (16%), nine had minor response (29%), and 17 had no response (55%), and Group C--one patient achieved complete response (3%), eight achieved partial response (27%), five had minor response (17%), and 16 had no response (53%). The median survival time for Group A was 9 months, for Group B was 9.5 months, and for Group C was 14 months. Intensifying the dose schedule of 5-FU by increasing the frequency of administration has significantly improved response rates. A prolongation of the median survival time of patients treated with a 48-hour infusion at 1-week intervals was noted, although this was not statistically significant.

Effects of subconjunctivally injected antineoplastic agents on three models of corneal inflammation.

Three models of corneal inflammation--acute toxic keratitis, phlyctenular keratitis and corneal graft rejection--were induced in rabbits and treated with subconjunctival injections of antineoplastic agents (methotrexate, cytosine arabinoside, 5-fluorouracil and 6-mercaptopurine) and Solu-Medrol (methylprednisolone sodium succinate). The inflammations responded to the drugs to various degrees when compared with the response in control animals treated with saline. Cytosine arabinoside effected a slight decrease in the clinical features of acute toxic keratitis, methotrexate was superior in decreasing inflammation and neovascularization in phlyctenular keratitis, and Solu-Medrol appeared to be the most useful in the treatment of graft rejection. When injected repeatedly, 5-fluorouracil tended to have significant toxicity in the presence of inflammation.

Ocular pharmacokinetics of subconjunctivally versus intravenously administered 6-mercaptopurine.

The levels of 6-mercaptopurine (6-MP) were measured in the anterior chamber aqueous, the vitreous and the serum of rabbits 0.5, 1, 2, 4, 8 and 12 hours following subconjunctival or intravenous injection of 10 mg/kg in 0.5 mL of saline, the maximum tolerated dose as determined experimentally. The mean peak concentrations of 6-MP in the aqueous and the vitreous respectively of the subconjunctivally injected eyes were 15 and 10 times those achieved in all the eyes following intravenous administration. The bioavailability of the drug over 12 hours was 21.67 micrograms/h in the aqueous and 22.22 micrograms/h in the vitreous following subconjunctival administration but only 1.47 and 3.50 micrograms/h respectively following intravenous administration. The serum concentration of 6-MP following subconjunctival injection was about half that following intravenous administration.

Treatment of ocular leukemia with local chemotherapy.

Two cases of human ocular leukemic recurrence were treated by combined local chemotherapy. Both cases were histologically proven with aspiration needle biopsy and successfully treated with subconjunctival injections of methotrexate, cytarabine, and corticosteroids.

Pharmacokinetics and metabolism of 5-fluorouracil following subconjunctival versus intravenous administration.

Two groups of six rabbits each were given 6.25 mg/kg of 6-carbon-14-labelled 5-fluorouracil (5-FU) either subconjunctivally or intravenously. The levels of the drug in the serum, the urine and the ocular humours 0.5, 1, 2, 4, 8 and 12 hours later were measured by high-pressure liquid chromatography, which distinguished between 5-FU and its metabolites. The peak levels of the parent drug in the serum and the urine were similar with the two routes of administration; however, compared with intravenous injection, subconjunctival injection resulted in 125 and 380 times the peak concentration of 5-FU in the anterior chamber aqueous and the vitreous respectively.

Subconjunctival versus intravenous cytosine arabinoside: effect of route of administration and ocular toxicity.

The ocular penetration, elimination, and toxicity of equidose cytosine arabinoside (Ara-C) (37.5 mg/kg) following subconjunctival versus intravenous injection were compared in rabbits. Drug levels were measured at 0.5, 1, 2, 4, 8, and 12 hours in serum, urine, and ocular compartments. Following subconjunctival administration, the peak concentration of Ara-C in the anterior chamber was 15 times and in the vitreous twice that obtained following intravenous administration. Drug levels obtained were considered high enough to be effective in inhibiting the growth of selected tumor lines. The cumulative urinary excretion over 12 hours was 67% and 70% for the subconjunctivally and intravenously injected animals, respectively, and peak serum levels were 0.061 mM and 0.170 mM, respectively. Clinical and histologic toxicity following subconjunctival injection was minimal, and no bone marrow suppression was detected at the dose level administered.

Combined local chemotherapy for a spontaneously occurring intraocular tumour in a cat.

A spontaneously occurring tumour in the anterior chamber of the eye of a cat was diagnosed by aspiration needle biopsy as a malignant lymphosarcoma. Combined local chemotherapy, consisting of subconjunctival injection of methylprednisolone acetate and methotrexate along with topical administration of dexamethasone, led to rapid resolution of the lesion. Over 18 weeks of follow-up there was no recurrence.

Steroid receptors in adjuvant hormonal therapy for breast cancer.

Using a computerized mathematical model the authors found that either a small [5%] or large [50%] hormone-dependent reduction in tumour cell population at the beginning of adjuvant chemotherapy for breast cancer greatly increases the probability fo achieving a cure. The fact that even a minor response to hormonal therapy early in the treatment of the tumor is effective underlines the importance of using estrogen receptors to to select potential responders in whom a cure is at least a strong theoretical possibility.

Concentrations of tritiated methotrexate in ocular compartments, serum and urine after subconjunctival and intravenous injection.

Forty-eight rabbits were given 6.25 mg/kg of tritiated methotrexate subconjunctivally or intravenously. Concentrations of the drug in ocular compartments, the serum and the urine were measured 0.5, 1, 2, 4, 8, 12, 24 and 48 hours after injection. Compared with intravenous administration subconjunctival injection resulted in 4.5 times more methotrexate in the anterior chamber, but the concentrations in the vitreous were the same with the two routes of administration. The serum levels of methotrexate, however, were nine times lower after subconjunctival injection.

Intraocular penetration of subconjunctivally administered 14C-fluorouracil in rabbits.

Fluorouracil is given for a variety of neoplasms by various administrative routes. Toxicity of susceptible normal tissue limits systemic dosage, but at this level intraocular tissue may not receive tumor-inhibiting concentrations. Subconjunctival administration of 6.25 mg of 14C-fluorouracil in 0.5-mL dosages resulted in a peak anterior chamber concentration of 69.5 micrograms/mL and a peak vitreous concentration of 10.5 micrograms/mL over the 12 hours tested. This resulted in no visible ocular damage. The intraocular levels achieved were greater than the concentration reported to inhibit selected tumors. The total dosage administered was considerably below the level of systemic toxicity.

The utilization of a clinical pharmacist--a way of decreasing medications in a community hospital.

This article summarizes the results of a study designed to evaluate clinical pharmacy services as a means of reducing drug usage in a 170-bed community hospital. A total of 591 medication orders for 93 hospitalized patients were evaluated. A pharmacy resident made recommendations regarding the appropriateness of the medication order to the attending physicians. A team of reviewing physicians later evaluated these recommendations. The resident's suggestions were also monitored by a university-affiliated and experienced clinical pharmacist. The number of medications ordered which the pharmacy resident would have prescribed during consultation with physicians was 312 (53 percent), while the overseeing clinical pharmacist would have prescribed 352 (60 percent). Two hundred and fifteen therapeutic recommendations were provided by the pharmacy resident, of which 38 (17.6 percent) were carried out by the attending physician. The reviewing physicians did not agree with 37 of these recommendations. Twenty-two drug interactions were detected, of which eleven were thought to be of definite clinical significance by the pharmacy resident. The study demonstrated that a 40 percent reduction in medication utilization could result in a community hospital, while the same level of therapeutic effectiveness was maintained, by using the services of a properly trained clinical pharmacist. The patient care appraisal committee which was appointed to evaluate the study reviewed the results and agreed that, based on the cost factor and improvement of patient care, clinical pharmacy services would be beneficial.